scholarly journals TELOMERE BIOLOGY: TELOMERE STRUCTURE, FUNCTION AND RELATED DISEASES

2020 ◽  
pp. 246-254
Author(s):  
Ranjan Kumar ◽  
Deepika Bhardwaj ◽  
Shikha Bharati ◽  
Manoj Kumar
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genome Integrity ◽  
Interacting Proteins ◽  
Eukaryotic Chromosome ◽  
Paper Detail ◽  
Key Words Telomere ◽  
Telomere Biology ◽  
Heterochromatin Structure ◽  
Telomere Structure

Telomere is the special heterochromatin structure which caps the end of eukaryotic chromosome and ensures the faithful replication of genetic materials. It also provides the protection against DNA damage signals and ensures the genome integrity and stability. Telomerase complete its task by its unique nucleoprotein structure. Here in this paper detail about nucleoprotein structure and their function is included. Robustness of function of telomere across cell cycle is guaranteed by the interaction between telomere and its interacting proteins. Recent findings regarding telomere biology and cancer are also included in this paper. KEY WORDS: Telomere, DNA damage, cell cycle, cancer

scholarly journals PP2A-Cdc55 is responsible for mitotic arrest in DNA re-replicating cells in S. cerevisiae

2020 ◽  
Author(s):  
Shoily Khondker ◽  
Amy E. Ikui
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Spindle Assembly Checkpoint ◽  
Mitotic Arrest ◽  
Cell Cycle Checkpoints ◽  
Genome Integrity ◽  
Cyclin Dependent Kinase ◽  
Metaphase Arrest ◽  
Daughter Cells ◽  
Origin Licensing

AbstractThe cell cycle is an ordered process in which cells replicate their DNA in S-phase and divide them into two identical daughter cells in mitosis. DNA replication takes place only once per cell cycle to preserve genome integrity, which is tightly regulated by Cyclin Dependent Kinase (CDK). Formation of the pre-replicative complex, a platform for origin licensing, is inhibited through CDK-dependent phosphorylation. Failure of this control leads to re-licensing, re-replication and DNA damage. Eukaryotic cells have evolved surveillance mechanisms to maintain genome integrity, termed cell cycle checkpoints. It has been shown that the DNA damage checkpoint is activated upon the induction of DNA re-replication and arrests cell cycle in mitosis in S. cerevisiae. In this study, we show that PP2A-Cdc55 is responsible for the metaphase arrest induced by DNA re-replication, leading to dephosphorylation of APC component, Exclusion of Cdc55 from the nucleus bypassed the mitotic arrest and resulted in enhanced cell lethality in re-replicating cells. The metaphase arrest in re-replication cells was retained in the absence of Mad2, a key component of the spindle assembly checkpoint. Moreover, re-replicating cells showed the same rate of DNA damage induction in the presence or absence of Cdc55. These results indicate that PP2A-Cdc55 maintains metaphase arrest upon DNA re-replication and DNA damage through APC inhibition.

scholarly journals The Role of UBR5 Mutations in the Pathogenesis of Mantle CELL Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4124-4124
Author(s):  
Olga Kutovaya ◽  
Stacy Hung ◽  
Hughes Christopher ◽  
Randy D Gascoyne ◽  
Morin Gregg ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cell Cycle ◽  
Dna Damage ◽  
Mantle Cell Lymphoma ◽  
Dna Damage Response ◽  
Cell Lymphoma ◽  
Interacting Proteins ◽  
Mantle Cell ◽  
Damage Response

Abstract Intro: Mantle cell lymphoma (MCL) accounts for 6% of non-Hodgkin lymphomas and represents a particularly challenging disease with patient outcomes inferior to most other lymphoma subtypes. Using targeted capture sequencing of MCL biopsy samples, we recently reported frequent mutations (18%) in UBR5, a gene encoding an E3 ubiquitin-protein ligase that has not been previously implicated in lymphomagenesis. All mutations were clustered within 100bp in or around exon 58 of UBR5 and truncate the reading frame or change a key lysine residue. These mutations are predicted to result in the loss of the conserved cysteine residue in the HECT-domain, which is responsible for binding the ubiquitin co-factor. The recurrence and clustering of UBR5 mutations suggest their critical pathogenic involvement in a subgroup of MCL that might be therapeutically targetable. The aim of this study is to determine UBR5 mutation-associated proteome changes and altered cell signaling. Methods: As seen in MCL patients, mutations in exon 58 of UBR5 were introduced to three MCL cell lines (Granta-519, Jeko-1, and Mino) using the CRISPR-Cas9 genome engineering tool. First, mass spectrometry-based immunoprecipitation proteomics (IP-MS) was employed to identify differences in UBR5 interacting partners between UBR5 mutant and wildtype (WT) cells. Candidate UBR5 interacting proteins were validated by flow cytometry, western blotting, co-immunoprecipitation, and immunofluorescence. Next, global proteomes of UBR5 mutants and WT were analyzed by Tandem Mass Tag (TMT)-based mass spectrometry quantification to identify proteins with differential expression due to the UBR5 mutations. Results: The IP-MS analysis of WT vs UBR5 mutants revealed histone and cell cycle control proteins as candidate differential UBR5 interacting proteins (p<0.05). Particularly, histones H1, H4, and H2AFX, as well as the cell cycle genes CDC5L, BUB3, MAP4, RAD50 and CDK11B were identified as candidate UBR5 interacting partners. The global proteome analysis identified a set of differentially expressed genes (mutant vs wt; p<0.05) that are common among the MCL cell lines with the same direction of change. Gene ontology analysis of this set revealed DNA damage response, chromosome organization, and cell cycle response pathways as the predominant pathways affected. Moreover, our preliminary functional studies indicate constitutive phosphorylation of H2AFX in UBR5 mutants vs WT in line with the role of UBR5 in DNA damage response. Conclusions: Our results are consistent with UBR5 functioning as a key regulator of cell signalling and strongly suggest UBR5 as a novel regulator of histone modifications and DNA damage response. These findings provide an experimentally valid platform for further functional investigation and testing of target therapies for MCL harbouring UBR5 mutations. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mechanosensing by the lamina protects against nuclear rupture, DNA damage, and cell cycle arrest

2019 ◽  
Author(s):  
Sangkyun Cho ◽  
Manasvita Vashisth ◽  
Amal Abbas ◽  
Stephanie Majkut ◽  
Kenneth Vogel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cell Types ◽  
Genome Integrity ◽  
Lamin A ◽  
Cycle Arrest ◽  
Nonmuscle Cell ◽  
Repair Factor ◽  
Nuclear Rupture

SummaryWhether cell forces or extracellular matrix (ECM) can impact genome integrity is largely unclear. Here, acute perturbations (~1hr) to actomyosin stress or ECM elasticity cause rapid and reversible changes in lamin-A, DNA damage, and cell cycle. Embryonic hearts, differentiated iPS-cells, and various nonmuscle cell types all show that actomyosin-driven nuclear rupture causes cytoplasmic mis-localization of DNA repair factors and excess DNA damage. Binucleation and micronuclei increase as telomeres shorten, which all favor cell cycle arrest. Deficiencies in lamin-A and repair factors exacerbate these effects, but lamin-A-associated defects are rescued by repair factor overexpression and by contractility modulators in clinical trials. Contractile cells on stiff ECM normally exhibit low phosphorylation and slow degradation of lamin-A by matrix-metalloprotease-2 (MMP2), and inhibition of this lamin-A turnover and also actomyosin contractility is seen to minimize DNA damage. Lamin-A is thus stress-stabilized to mechano-protect the genome.

scholarly journals Adaptation to DNA damage as a bet-hedging mechanism in a fluctuating environment

2021 ◽  
Author(s):  
Pierre Roux ◽  
Delphine Salort ◽  
Zhou Xu
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
Cell Survival ◽  
Genome Instability ◽  
Population Level ◽  
Signalling Pathway ◽  
Genome Integrity ◽  
Dna Damage Checkpoint ◽  
Bet Hedging

AbstractIn response to DNA damage, efficient repair is essential for cell survival and genome integrity. In eukaryotes, the DNA damage checkpoint is a signalling pathway that coordinates this response and arrests the cell cycle to provide time for repair. However, when repair fails or when the damage is not repairable, cells can eventually bypass the DNA damage checkpoint and undergo cell division despite persistent damage, a process called adaptation to DNA damage. Interestingly, adaptation occurs with a delayed timing compared to repair and shows a large variation in time, two properties that may provide a survival advantage at the population level without interfering with repair. Here, we explore this idea by mathematically modelling cell survival in response to DNA damage and focusing on adaptation parameters. We find that the delayed adaptation timing indeed maximizes survival, but its heterogeneity is beneficial only in a fluctuating damage-inducing environment. Finally, we show that adaptation does not only contribute to survival but also to genome instability and mutations, which might represent another criterion for its selection through-out evolution. Overall, we propose that adaptation can act as a bet-hedging mechanism for cell survival in response to DNA damage.

scholarly journals Adaptation to DNA damage as a bet-hedging mechanism in a fluctuating environment

2021 ◽  
Vol 8 (8) ◽  
pp. 210460
Author(s):  
Pierre Roux ◽  
Delphine Salort ◽  
Zhou Xu
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
Cell Survival ◽  
Genome Instability ◽  
Population Level ◽  
Signalling Pathway ◽  
Genome Integrity ◽  
Dna Damage Checkpoint ◽  
Bet Hedging

In response to DNA damage, efficient repair is essential for cell survival and genome integrity. In eukaryotes, the DNA damage checkpoint is a signalling pathway that coordinates this response and arrests the cell cycle to provide time for repair. However, when repair fails or when the damage is not repairable, cells can eventually bypass the DNA damage checkpoint and undergo cell division despite persistent damage, a process called adaptation to DNA damage. Interestingly, adaptation occurs with a delayed timing compared with repair and shows a large variation in time, two properties that may provide a survival advantage at the population level without interfering with repair. Here, we explore this idea by mathematically modelling cell survival in response to DNA damage and focusing on adaptation parameters. We find that the delayed adaptation timing indeed maximizes survival, but its heterogeneity is beneficial only in a fluctuating damage-inducing environment. Finally, we show that adaptation does not only contribute to survival but also to genome instability and mutations, which might represent another criterion for its selection throughout evolution. Overall, we propose that adaptation can act as a bet-hedging mechanism for cell survival in response to DNA damage.

scholarly journals Jiri Lukas: Visualizing genome integrity maintenance

2012 ◽  
Vol 198 (1) ◽  
pp. 4-5
Author(s):  
Caitlin Sedwick
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genome Integrity

Lukas studies how cells detect and deal with DNA damage throughout the cell cycle.

scholarly journals When genome integrity and cell cycle decisions collide: roles of polo kinases in cellular adaptation to DNA damage

2014 ◽  
Vol 8 (3) ◽  
pp. 195-203 ◽  
Author(s):  
Diego Serrano ◽  
Damien D’Amours
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genome Integrity ◽  
Cellular Adaptation

scholarly journals An adaptive pre-DNA-damage-response protects genome integrity

2020 ◽  
Author(s):  
Sandrine Ragu ◽  
Gabriel Matos-Rodrigues ◽  
Nathalie Droin ◽  
Aurélia Barascu ◽  
Sylvain Caillat ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Cell Cycle Progression ◽  
Replication Stress ◽  
Nuclear Accumulation ◽  
Genome Integrity ◽  
Cycle Progression ◽  
Stress Threshold ◽  
Damage Response

AbstractThe DNA damage response (DDR) interrupts cell cycle progression to restore genome integrity. However, unchallenged proliferating cells are continually exposed to endogenous stress, raising the question of a stress-threshold for DDR activation. Here, we identified a stress threshold below which primary human fibroblasts, activate a cell-autonomous response that not activates full DDR and not arrests cell cycle progression,. We characterized this “pre-DDR” response showing that it triggers the production of reactive oxygen species (ROS) by the NADPH oxidases DUOX1 and DUOX2, under the control of NF-κB and PARP1. Then, replication stress-induced ROS (RIR) activates the FOXO1 detoxifying pathway, preventing the nuclear accumulation of the pre-mutagenic 8-oxoGuanine lesion, upon endogenous as well as exogenous pro-oxidant stress. Increasing the replication stress severity above the threshold triggers the canonical DDR, leading to cell cycle progression arrest, but also to RIR suppression. These data reveal that cells adapt their response to stress severity, unveiling a tightly regulated ”pre-DDR” adaptive response that protects genome integrity without arresting cell cycle progression.

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